Aripiprazole is a pharmaceutical compound having the IUPAC name 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one, which is represented by Formula 1:

Aripiprazole is a dopaminergic neurotransmitter antagonist. Aripiprazole belongs to a group of carbostyril derivatives that can be used as atypical antipsychotics and antidepressants for schizophrenia, bipolar disorder, clinical depression, and the like (Patent Documents 1 and 2).
Aripiprazole is already known in the literature and more detailed pharmacological mechanisms, pharmacokinetics, synthesis methods, and side effects thereof can be understood from the disclosures of known references, for example, Non-Patent Document 1. Thus, Non-Patent Document 1 is incorporated herein by reference in its entirety and the following references are also incorporated herein by reference in their entireties.
Aripiprazole formulations in the form of tablets are widely commercially available (Abilify™, Otsuka Pharmaceutical Co.). For more successful treatment for schizophrenia, easy-to-take formulations are used in preference to swallowing tablets. That is, patients prefer orally disintegrating formulations to tablets and oral solutions that are difficult to swallow (Non-Patent Document 2).
In view of this, antipsychotics including aripiprazole as an active ingredient are presented in the form of orally disintegrating formulations, such as chewable tablets and rapidly dissolving films, as well as swallowing tablets. Conventional orally disintegrating formulations can be understood, for example, from Patent Document 3, which discloses a flash-melt oral dosage formulation of aripiprazole.
Orally disintegrating formulations of aripiprazole increase the convenience of administration for patients but cause the patients to feel bitterness peculiar to aripiprazole, resulting in an unfavorable feeling upon taking (Non-Patent Document 3).
To solve such problems, there have been developed, for example, techniques for encapsulating aripiprazole with polymeric materials (see Non-Patent Document 4) and techniques for constituting hybrid systems of aripiprazole with layered clay materials to suppress dissolution of the aripiprazole in the oral cavity (for example, Patent Document 4 discloses an aripiprazole-bentonite-AEA (polyvinyl acetal-diethyl-acetate) hybrid for masking a bitter taste of aripiprazole). However, these techniques have the problems of low dissolution rate and bioavailability of aripiprazole.
The problems of the prior art are explained by the fact that aripiprazole per se has a very low solubility in water (about 0.00001 w/v % at 25° C.), which directly leads to low bioavailability (see Non-Patent Document 5). Another reason is that when the dissolution of aripiprazole in the oral cavity is suppressed for the purpose of masking a bitter taste of aripiprazole, the dissolution rate of aripiprazole is considerably reduced, eventually increasing the possibility of poor bioavailability.
The low solubility of aripiprazole affects the dissolution rate of aripiprazole, leading to poor bioavailability. In this regard, an improvement in the solubility of aripiprazole is considered a very important technical solution in aripiprazole formulations, apart from bitterness masking.
The solubility of aripiprazole is pH-dependent and decreases with increasing pH. Particularly, it was found that aripiprazole has poor bioavailability at a pH exceeding 5 due to its low solubility (see Non-Patent Document 5).
Thus, most conventional aripiprazole formulations have been designed to be dissolved in low pH environments or have relatively low pH values.
Unlike a swallowing tablet or an oral solution whose retention time in the oral cavity is very short, an orally disintegrating formulation, particularly an orally fast dissolving film formulation, stays in the oral cavity for a relatively long time because the drug tends to disintegrate in the oral cavity, and therefore, its low pH causes serious damage to the oral tissues.
Particularly, teeth were found to undergo enamel demineralization at a pH of 5.7 or less, which is a cause of dental caries (see Non-Patent Document 6 and Non-Patent Document 7). For this reason, pH 5.7 is a critical point where teeth begin to decay and is considered as a reference point to determine what food causes tooth decay.
Particularly, aripiprazole is mainly prescribed for schizophrenia. Schizophrenia is treated by administration of a suppressive drug over a long period of time. The long-term administration of a formulation having a low pH inevitably causes damage to oral tissues such as teeth.
Under such circumstances, there is an urgent need for an orally fast dissolving film formulation that does not deteriorate the dissolution rate of aripiprazole while maintaining its pH at a level where the risk of dental caries in the mouth can be avoided.
There is another urgent need for an orally fast dissolving film formulation that can mask bitterness of aripiprazole without deteriorating the dissolution rate of aripiprazole.